Assembly of the Auditory Circuitry by a Hox Genetic Network in the Mouse Brainstem

Rhombomeres (r) contribute to brainstem auditory nuclei during development. Hox genes are determinants of rhombomere-derived fate and neuronal connectivity. Little is known about the contribution of individual rhombomeres and their associated Hox codes to auditory sensorimotor circuitry. Here, we show that r4 contributes to functionally linked sensory and motor components, including the ventral nucleus of lateral lemniscus, posterior ventral cochlear nuclei (VCN), and motor olivocochlear neurons. Assembly of the r4-derived auditory components is involved in sound perception and depends on regulatory interactions between Hoxb1 and Hoxb2. Indeed, in Hoxb1 and Hoxb2 mutant mice the transmission of low-level auditory stimuli is lost, resulting in hearing impairments. On the other hand, Hoxa2 regulates the Rig1 axon guidance receptor and controls contralateral projections from the anterior VCN to the medial nucleus of the trapezoid body, a circuit involved in sound localization. Thus, individual rhombomeres and their associated Hox codes control the assembly of distinct functionally segregated sub-circuits in the developing auditory brainstem

Towards brain-tissue-like biomaterials

Many biomaterials have been developed which aim to match the elastic modulus of the brain for improved interfacing. However, other properties such as ultimate toughness, tensile strength, poroviscoelastic responses, energy dissipation, conductivity, and mass diffusivity also need to be considered

Constriction imposed by basement membrane regulates developmental cell migration

The basement membrane (BM) is a specialized extracellular matrix (ECM), which underlies or encases developing tissues. Mechanical properties of encasing BMs have been shown to profoundly influence the shaping of associated tissues. Here, we use the migration of the border cells (BCs) of the Drosophila egg chamber to unravel a new role of encasing BMs in cell migration. BCs move between a group of cells, the nurse cells (NCs), that are enclosed by a monolayer of follicle cells (FCs), which is, in turn, surrounded by a BM, the follicle BM. We show that increasing or reducing the stiffness of the follicle BM, by altering laminins or type IV collagen levels, conversely affects BC migration speed and alters migration mode and dynamics. Follicle BM stiffness also controls pairwise NC and FC cortical tension. We propose that constraints imposed by the follicle BM influence NC and FC cortical tension, which, in turn, regulate BC migration. Encasing BMs emerge as key players in the regulation of collective cell migration during morphogenesis

A glimpse in critical attributes to design cutaneous film forming systems based on ammonium methacrylate

A film forming system based on Eudragit\uae RL (EuRL) was designed aiming to evidence the relevance of formulative variables on the following critical attributes: film forming rate, outward stickiness, Young modulus (Y) and in vitro drug skin permeation. Different solvent mixtures (acetone and isopropanol in the range from 10:90 to 40:60 v/v), polymer concentrations (10-30 % w/w), and plasticizer types and concentrations (triacetin or tributyl citrate, up to 50% of EuRL) were evaluated. EuRL dissolved in 80/20 or 70/30 v/v isopropanol/acetone mixtures at the concentration of 20% and plasticized with tributyl citrate (20 or 30% with respect to polymer) gave films with negligible stickiness and Y lower than 3 MPa. This value should assure an intimate and prolonged contact with the skin since it was significantly lower than Y of human stratum corneum (55 MPa). The optimized formulations were able to sustain the skin permeation of ibubrofen, ketoprofen and flurbiprofen and evidenced the importance of each formulative variable. In particular, relatively slow solvent evaporation rate can determine an initial \u201cburst\u201d effect and can influence the drug permeation in the initial hours. Conversely, when the solvent evaporation rate is not discriminant, the thermodynamic activity remains the main parameter driving the skin permeation

Müller glia provide essential tensile strength to the developing retina.

This is the final version of the article. It first appeared from the Rockefeller University Press via http://dx.doi.org/10.1083/jcb.201503115To investigate the cellular basis of tissue integrity in a vertebrate central nervous system (CNS) tissue, we eliminated Müller glial cells (MG) from the zebrafish retina. For well over a century, glial cells have been ascribed a mechanical role in the support of neural tissues, yet this idea has not been specifically tested in vivo. We report here that retinas devoid of MG rip apart, a defect known as retinoschisis. Using atomic force microscopy, we show that retinas without MG have decreased resistance to tensile stress and are softer than controls. Laser ablation of MG processes showed that these cells are under tension in the tissue. Thus, we propose that MG act like springs that hold the neural retina together, finally confirming an active mechanical role of glial cells in the CNS.This work was funded by a Herchel Smith Postdoctoral Fellowship to R.B.M., the Wellcome Trust programme in Developmental Biology to O.R. and J.O., NIH grants EY14358 (R.O.W.) and EY01730 (Vision Core), MRC Career Development Award and HFSP Young Investigator Grant to K.F., and a Wellcome Trust Investigator Award to W.A.H

Cortical cell stiffness is independent of substrate mechanics

Cortical stiffness is an important cellular property that changes during migration, adhesion and growth. Previous atomic force microscopy (AFM) indentation measurements of cells cultured on deformable substrates have suggested that cells adapt their stiffness to that of their surroundings. Here we show that the force applied by AFM to a cell results in a significant deformation of the underlying substrate if this substrate is softer than the cell. This ‘soft substrate effect’ leads to an underestimation of a cell’s elastic modulus when analysing data using a standard Hertz model, as confirmed by finite element modelling and AFM measurements of calibrated polyacrylamide beads, microglial cells and fibroblasts. To account for this substrate deformation, we developed a ‘composite cell–substrate model’. Correcting for the substrate indentation revealed that cortical cell stiffness is largely independent of substrate mechanics, which has major implications for our interpretation of many physiological and pathological processes

Towards brain-tissue-like biomaterials

Many biomaterials have been developed which aim to match the elastic modulus of the brain for improved interfacing. However, other properties such as ultimate toughness, tensile strength, poroviscoelastic responses, energy dissipation, conductivity, and mass diffusivity also need to be considered

Mechanosensing is critical for axon growth in the developing brain.

During nervous system development, neurons extend axons along well-defined pathways. The current understanding of axon pathfinding is based mainly on chemical signaling. However, growing neurons interact not only chemically but also mechanically with their environment. Here we identify mechanical signals as important regulators of axon pathfinding. In vitro, substrate stiffness determined growth patterns of Xenopus retinal ganglion cell axons. In vivo atomic force microscopy revealed a noticeable pattern of stiffness gradients in the embryonic brain. Retinal ganglion cell axons grew toward softer tissue, which was reproduced in vitro in the absence of chemical gradients. To test the importance of mechanical signals for axon growth in vivo, we altered brain stiffness, blocked mechanotransduction pharmacologically and knocked down the mechanosensitive ion channel piezo1. All treatments resulted in aberrant axonal growth and pathfinding errors, suggesting that local tissue stiffness, read out by mechanosensitive ion channels, is critically involved in instructing neuronal growth in vivo.This work was supported by the German National Academic Foundation (scholarship to D.E.K.), Wellcome Trust and Cambridge Trusts (scholarships to A.J.T.), Winston Churchill Foundation of the United States (scholarship to S.K.F.), Herchel Smith Foundation (Research Studentship to S.K.F.), CNPq 307333/2013-2 (L.d.F.C.), NAP-PRP-USP and FAPESP 11/50761-2 (L.d.F.C.), UK EPSRC BT grant (J.G.), Wellcome Trust WT085314 and the European Research Council 322817 grants (C.E.H.); an Alexander von Humboldt Foundation Feodor Lynen Fellowship (K.F.), UK BBSRC grant BB/M021394/1 (K.F.), the Human Frontier Science Program Young Investigator Grant RGY0074/2013 (K.F.), the UK Medical Research Council Career Development Award G1100312/1 (K.F.) and the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number R21HD080585 (K.F.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/nn.439

Rural continental aerosol properties and processes observed during the Hohenpeissenberg Aerosol Characterization Experiment (HAZE2002)

International audienceDetailed investigations of the chemical and microphysical properties of rural continental aerosols were performed during the HAZE2002 experiment, which was conducted in May 2002 at the Meteorological Observatory Hohenpeissenberg (DWD) in Southern Germany. Online measurements included: Size-resolved chemical composition of submicron particles; total particle number concentrations and size distributions over the diameter range of 3 nm to 9 ?m; gas-phase concentration of monoterpenes, CO, O3, OH, and H2SO4. Filter sampling and offline analytical techniques were used to determine: Fine particle mass (PM2.5), organic, elemental and total carbon in PM2.5 (OC2.5, EC2.5, TC2.5), and selected organic compounds (dicarboxylic acids, polycyclic aromatic hydrocarbons, proteins). Overall, the non-refractory components of submicron particles detected by aerosol mass spectrometry (PM1, 6.6±5.4 ?g m?3, arithmetic mean and standard deviation) accounted for ~62% of PM2.5 determined by filter gravimetry (10.6±4.7 ?g m?3). The relative proportions of non-refractory submicron particle components were: (23±39)% ammonium nitrate, (27±23)% ammonium sulfate, and (50±40)% organics (OM1). OM1 was closely correlated with PM1 (r2=0.9) indicating a near-constant ratio of non-refractory organics and inorganics. The average ratio of OM1 to OC2.5 was 2.1±1.4, indicating a high proportion of heteroelements in the organic fraction of the sampled rural aerosol. This is consistent with the high ratio of oxygenated organic aerosol (OOA) over hydrocarbon-like organic aerosol (HOA) inferred from the AMS results (4:1), and also with the high abundance of proteins (~3%) indicating a high proportion of primary biological material (~30%) in PM2.5. This finding was confirmed by low abundance of PAHs (?3) and EC (?3) in PM2.5 and detection of several secondary organic aerosol compounds (dicarboxylic acids) and their precursors (monoterpenes). New particle formation was observed almost every day with particle number concentrations exceeding 104 cm?3 (nighttime background level 1000?2000 cm?3). Closer inspection of two major events indicated that the observed nucleation agrees with ternary H2SO4/H2O/NH3 nucleation and that condensation of both organic and inorganic species contributed to particle growth